Medical Hypotheses 145 (2020) 110332

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Dysimmunity and inflammatory storm: Watch out for bone lesions in T

COVID-19 infection
Huaqiang Tao1, Gaoran Ge1, Wenming Li1, Xiaolong Liang, Hongzhi Wang, Ning Li, Houyi Sun,
Wei Zhang, Dechun Geng
⁎

Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215000, China

ARTICLE INFO ABSTRACT

Keywords: At the end of 2019, a new kind of pneumonia which was proven to be supported by novel coronaviruses named
COVID-19 SARS-CoV-2 emerges and it seems to be more complicate in its clinical course and management. Related re-
SARS-CoV-2 searches have demonstrated that SARS-CoV-2 serves roles in respiratory, intestinal and neuronal diseases. Given
Dysimmunity the growing cases of COVID-19, analyzing the relevance between COVID-19 and fragile patients who suffer from
Inflammatory storm
bone destruction is entirely indispensable. Accordingly, the recapitulatory commentary is necessary to advance
Bone lesions
our knowledge on COVID-19 and orthopedics. In this article, we particularly clarify the possible relationship
between the newly COVID-19 infection and bone lesions from the standpoints of dysimmunity and inflammatory
storm.

Introduction to defend against viral infection and dissemination at the entry site [5].

It has been approved that inflammation-induced pathogenesis in Hypotheses

COVID-19 infection has a strong correlation with incidence of cardio-
vascular metabolic diseases and gastrointestinal injury [1]. Simulta-
neously, oxidative stress and inflammation responses as interdependent
and interconnected processes that co-exist in the inflame milieu [2].
The pneumonia patients constantly suffer from hypoxaemia. Senile
patients with SARS-CoV-2 infection always stand perennial disability,
such as pulmonary fibrosis and respiratory insufficiency [3]. Bone owns
a quite hypoxic microenvironment, the hypoxia of organism will affect
heterogeneous pO2 in bone marrow in a degree.
Not only those inflammatory responses, but also the innate immune
system is biologically intertwined with the processes of bone home-
ostasis. When subjected to SARS-CoV-2, host cell-mediated and hu-
moral immune responses are rapidly activated and take defensive
measures [4]. Massive immune cells were recruited in alveolar cells as
the disease progresses. To initiate an antiviral response, Pattern re-
cognition receptors (PRRs) were involved in innate immune responses
to identify the invasion of the virus. This recognition event results in the
activation of downstream signaling cascade, including NF-κB, activator
protein1 (AP-1) and interferon regulatory factor-3 (IRF3). Con-
comitantly, these transcription proteins translocate into nuclear and
prompt expression of type 1 IFNs and other pro-inflammatory cytokines
As for severe COVID-19 infection, Huang et al. found that patients
who need ICU monitoring had much higher concentrations of cytokines
and chemokines than other ones, such as IL-1β, IFN-α, IL-1RA and IL-8,
suggesting that the inflammatory storm was involved in infection se-
verity [6]. Significantly high release of blood pro-inflammatory med-
iators also responds to lung injury and viral replication, including TNF-
α, IL-2, IL-10 and IP-10. However, studies on the correlation between
pro-inflammatory cytokine responses and bone metabolism in COVID-
19 patients are still lacking. In this special background, will in-
flammatory disorder and immune imbalance affect bone metabolism
after COVID-19 infection?
Justification of proposed hypotheses
The role of inflammatory factors has been closely associated with
bone loss and early osteoclastogenesis [7]. It has been reported that the
deficiency of ACE2 in mesenchymal stem cells (MSCs) increases the
expression of TNF-α, which may be responsible for skeleton dysfunction
and adverse structure outcomes [8]. As is accepted, inflammatory cy-
tokines promote osteoclastogenesis by regulating RANK/RANKL/OPG

⁎
Corresponding author at: Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188, shi zi Road, Suzhou 215006, China.
E-mail address: szgengdc@suda.edu.cn (D. Geng).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.mehy.2020.110332
Received 19 September 2020; Received in revised form 29 September 2020; Accepted 1 October 2020
Available online 06 October 2020
0306-9877/ © 2020 Elsevier Ltd. All rights reserved.
H. Tao, et al.
axis in direct [9]. Concretely, they drive up bone resorption by pro-
moting RANK expression on monocytes. At the same time, they
downregulate osteoblastic production by restraining OPG. It’s con-
jecturable that, if RANKL is not resolved by normal homeostatic system,
the inflammation stimuli initiated by SARS-CoV-2 can become chronic
in nature and lead to the secretion of a plenty of pro-inflammatory
cytokines. In these signaling cascades of osteoclastogenesis, it is quite
evident that TNF-α regulate the activation of calcium signaling and the
auto-amplification of NFATc1, which has an active acceleration in os-
teoclast expression [10]. Some other pro-inflammatory cytokines, such
as IL-1β and IL-2, have also been studied in the context of bone loss or
arthritis [11,12]. In parallel, inflammation storm seems to share the
commonness in the progress of bone healing. Dysregulated inflamma-
tion responses lead to increased bone resorption, thereby leading to
subsequent bone destruction and arthritis.
Hypoxia signaling is an intervention factor for osteoclast differ-
entiation and osteoblast formation. Literature indicates that hypoxia
boosts the overproduction of pro-osteoclastogenic cytokines, including
receptor activator of nuclear factor-B ligand (RANKL), vascular en-
dothelial growth factor (VEGF), macrophage colony-stimulating-factor
(M-CSF), leading to osteoclasts activation [13]. Simultaneously, hy-
poxia inducible factor (HIF-1) was proven to facilitate osteoclast dif-
ferentiation by overexpressing RANKL and nuclear factor of activated T
cells cytoplasmic 1 (NFATc1) [14]. As for osteoblasts, hypoxia signaling
seems to exhibit inactive effects on osteogenesis capacity, which was
linked to angiogenesis-induced bone-forming and the intervention of
canonical osteoblastic Wnt signaling [15,16]. Therefore, SARS-CoV-2
induced hypoxaemia is most likely to mediate bone destruction and
disturb bone matrix.
The lack of oxygen reduces the energy supply of cell membrane. At
the same time, the metabolic disorder of oxygen evokes intracellular
free radicals to damage membrane transport proteins [17]. The dele-
terious effects of oxidative stress in bone metabolism have elicited
much attention in recent years. Oxygen free radicals, especially reactive
oxygen species, maintain homergy in bone biology. An extensive
variety of intracellular signaling events are involved in osteoclast ac-
tivation, including the regulation of mitogen-activated protein kinases
(MAPKs) and intracellular Ca2+ levels [18]. In addition, excessive free
radicals hamper osteoblast adhesion to worsen bone homeostasis in
further. Especially, hypoxaemia can also give rise to Ca2+ metabolism
disorder, which may injury osteocyte. With the imbalance between
oxygen delivery and consumption in COVID-19 patients, not only do we
need to search novel treatment for minimizing lung damage, but also
attract attention on succeeding hypoxia-induced cascade reactions in
the whole biological system.
As osteoblasts and osteoclasts exist in approach with immune cells
in medullary cavity, it’s no wonder that immune system shares massive
regulatory cytokines, signaling molecules and transcription factors with
bone biology. Osteoclasts take responsibility for bone resorption, which
share a collaborative precursor with macrophages and dendritic cells
[19]. In the antiviral innate immune, IRF3 emerges as a key molecule in
regulating immune responses. On the other hand, it has been found to
be associated with the expression of c-Jun and MARK, leading to
NFATc1 activation and bone loss [20]. The activation of NF-κB sig-
naling is directly associated with osteoclast differentiation and func-
tion. At the same time, it impairs both the differentiation of MSCs to-
wards the osteogenesis and osteoblast-mediated bone-forming capacity
[21]. Apart from that, NF-κB and AP-1 stimulate the expression of many
elements which required for inflammatory cytokines, driving up os-
teoclast activity and usually implicated inhibition on proliferation and
differentiation of osteoblasts [22].
In patients who suffered from SARS-CoV-2, lymphopenia is the most
common property, along with that is the drastically reduced numbers in
CD4+ T cells, CD8+ T cells and B cells [23]. Such patients exhibit a
proinflammatory state with functional defects in innate and adaptive
immune cell populations. In view of multiple cytokines of the adaptive
2
Medical Hypotheses 145 (2020) 110332
immune response serve dual roles in the regulation of skeleton, there is
a deeply rooted nexus between the immune system and skeletal
homeostasis. Various studies demonstrated that immune cells (B and T
cells), which secrete RANKL and TNF-α under a complicated internal
environment, facilitate osteoclast formation and bone resorption [24].
Moreover, especially T cells, can affect the differentiation and activity
of bone cells by a paracrine and juxtacrine pathway. Unlike T cells,
under physiological conditions, B cells are a significant source of os-
teoprotegerin (OPG) which is an important osteoclastogenesis in-
hibitory factor [25]. Analyzing the inner link, we can infer that immune
imbalance could disturb bone metabolism in a large extent, which ex-
hibit a tendency to bone destruction in immunization, although the
truth remains to be verified.
The management of COVID-19 in orthopedics
Patients with bone destructive diseases or fractures may confront a
greater risk of infection of COVID-19. Simultaneously, this virus can
affect the development of bone metabolism to a certain degree. We
should attach attention to SARS-CoV-2 infection-related bone destruc-
tion in the setting of this pandemic and beware of the clinical man-
agement of COVID-19 patients in orthopedics.
For patients who previously need orthopedic surgeries, we usually
firstly focus on the solution of virus infection. Considering that SARS-
CoV-2 may aggravate existing underlying disease and worsen bone
metabolism, if the cardiopulmonary function is acceptable the surgery,
the surgery should be operated on the basis of strict protection and
relevant surgical strategies should be formulated. The operation can be
performed using a minimally invasive approach and shorten the op-
eration time to reduce the amount of intraoperative bleeding and re-
duce operating room infection. At the same time, medical staff should
also pay attention to self-precautionary consciousness. Those entering
the operating room should be uniformly trained, including how to
properly donning and doffing protective clothing, hats, medicals masks,
latex gloves, etc. Finally, medical waste needs to be trained in a unified
manner. The rooms of pneumonia caused by the novel coronavirus
should be single. We should remain vigilant and monitor the develop-
ment of fever and respiratory symptoms as well.
For infected patients who are free from bone lesions, health edu-
cation is a major method of controlling risk factors. We need to inform
the patients about the possible bone destruction and joint inflammation
through the health education. Similarly, the mental health of the pa-
tient cannot be ignored. Meanwhile, regular exercise or physical ac-
tivity practice should be carried on, not only can it strengthen the im-
mune system to defend infection, but also have a positive effect on bone
quality and strength. For the infected elderly who have taken a turn for
the better, it’s important to routinely supplement calcium and vitamin
D3 to prevent decreased bone matrix. Apart from that, combining to the
therapeutic experiences from SARS-CoV, we especially need to pay at-
tention to the prescription and avoide the occurrence of femoral head
necrosis steroids [26].
Conclusions
It’s conjecturable that cytokine storm-induced systemic inflamma-
tion and immunologic dissonance ultimately increase bone resorption
and restrain bone formation in bone marrow microenvironment.
Various kinds of pathological factors seem to share undesirable com-
monness in the process of bone healing. In clinic, it’s essential to take
precautions against the incidence of bone destruction and arthritis as-
sociated with COVID-19. Standard interventions to manage is the
foundation of nursing and we need a team-based care model to resolve
orthopedic problem in this special background.
H. Tao, et al.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgement
This study was supported by the National Natural Science
Foundation of China (81873991, 81771885, 81672238, 81472077,
81572183, 91849114 and 81472105).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.mehy.2020.110332.
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